Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Biomedical Sciences Graduate Program, Penn State College of Medicine, Hershey, PA.
J Cell Biol. 2021 Aug 2;220(8). doi: 10.1083/jcb.202008101. Epub 2021 May 26.
Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
癌基因诱导的衰老（OIS）是正常细胞在癌基因激活时发生的一种稳定的细胞周期停滞。经历 OIS 的细胞表达广泛的分泌因子，这些因子会影响衰老微环境，称为衰老相关分泌表型（SASP），其在特定情况下可能有益或有害。OIS 细胞还具有明显的表观遗传变化。我们全面评估了 OIS 细胞的组蛋白修饰，发现 H3K79me2/3 的活性组蛋白标记增加。端粒沉默 1 样蛋白（DOT1L）的 H3K79 甲基转移酶破坏剂对于 IL1A 基因座处 H3K79me2/3 占有率的增加是必要且充分的，但对于其他 SASP 基因则不然，并且是 STING 的下游。调节 DOT1L 的表达并不影响细胞周期停滞。总之，我们的研究确立了 DOT1L 作为 SASP 的表观遗传调节剂，其表达与衰老相关的细胞周期停滞脱钩，为抑制衰老的负面影响提供了一种潜在策略，同时保持对增殖的有益抑制。
